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Acquired (adaptive) immunity.pdf

  1. 1. Acquired (adaptive) immunity ⚫ The resistance that human acquires during life is known as acquired immunity. ⚫ Also known as adaptive immunity. ⚫ Acquired immunity is caused by a special immune system that forms antibodies and/or activated lymphocytes that attack and destroy the specific invading organism or toxin.
  2. 2. Adaptive immunity: Basic type Humoral immune response (HIR) or B-cell immunity ⚫ B-lymphocytes ⚫ mediated by antibodies ⚫ eliminate extra-cellular microbes and their toxins Cell-mediated immune response (CMIR) or T-cell immunity ⚫ T-lymphocytes ⚫ eliminate intracellular microbes that survive within phagocytes or other infected cells
  3. 3. Antigens ⚫ an antigen is a molecule capable of inducing an immune response (to produce an antibody) in the host organism. ⚫ In general, these are proteins or large polysaccharides, ⚫ antigens (antibody generations). ⚫ For a substance to be antigenic, it usually must have a high molecular weight of 8000 or greater.
  4. 4. B-Lymphocyte ⚫ B lymphocytes are formed in the liver during mid fetal life and in the bone marrow during late fetal life and after birth. ⚫ B lymphocyte was first discovered in birds, which have a special pre-processing organ called the bursa of Fabricius. For this reason, these lymphocytes are called “B” lymphocytes to designate the role of the bursa
  5. 5. ⚫ immature B cells migrate from the bone marrow in the lymphoid organs such as the spleen and lymph nodes which receive a constant supply of antigen through circulating lymph. ⚫ The B lymphocytes actively secrete antibodies that are the reactive agents and are capable of combining with and destroying the antigenic substance. ⚫ B lymphocytes have greater diversity than the T lymphocytes, thus forming many millions of types of B-lymphocyte antibodies
  6. 6. B cell development ⚫ B cells undergo two types of selection while developing in the bone marrow to ensure proper development, both involving B cell receptors (BCR) on the surface of the cell. ⚫ Positive selection If the B cell receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop. ⚫ Negative selection occurs through the binding of self-antigen with the BCR. If the BCR bind strongly to self-antigen, then the B cell undergoes clonal deletion or clonal anergy. ⚫ This negative selection process leads to a state of central tolerance, in which the mature B cells do not bind self antigens present in the bone marrow
  7. 7. ⚫ B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes. ⚫ After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph. ⚫ At the SLO, B cell activation begins when the B cell binds to an antigen.
  8. 8. T and B lymphocyte formation
  9. 9. Humoral Immunity And The Antibodies Formation of antibody: ⚫ Upon entry of a foreign antigen, macrophages in lymphoid tissue phagocytize the antigen and then present it to adjacent B lymphocytes. ⚫ The B lymphocytes specific for the antigen immediately enlarge and take on the appearance of lymphoblasts. ⚫ Some of the lymphoblasts further differentiate to form plasmablasts.
  10. 10. ⚫ The plasmablasts then divide slowly over to form plasma cell. ⚫ plasma cell then produces gamma globulin antibodies at an extremely rapid rate—about 2000 molecules per second for each plasma cell. ⚫ This process continues for several days or weeks until finally exhaustion and death of the plasma cells occur.
  11. 11. ⚫ Plasma cells can be generally divided into two distinct categories based on their lifespan:  (a) short-lived plasma cells/plasmablasts (proliferating cells with a life span of 3–5 days) and  (b) long-lived plasma cells (non-proliferating cells with a life span of several months to lifetime). ⚫ The short-lived plasma cells provide rapid protection but undergo apoptosis after a few days of intense antibody secretion. ⚫ However, the long-lived plasma cells reside in tissues such as the bone marrow and gut- associated lymphoid tissue and can continue producing antibodies for many years, providing lifelong immunity against infectious diseases such as measles and smallpox
  12. 12. B cell activation and Function
  13. 13. Memory cells formation: ⚫ Few of the lymphoblasts formed by do not go on to form plasma cells but instead form moderate numbers of new B lymphocytes similar to those of the original clone. ⚫ The B-cell population of the specifically activated clone becomes greatly enhanced. ⚫ These lymphocytes are called memory cells. ⚫ Subsequent exposure to the same antigen will cause a much more rapid and much more potent antibody response this second time
  14. 14. Antibodies ⚫ Antibodies are gamma globulins called immunoglobulins (Ig) that have molecular weights between 160,000 and 970,000 Dalton and constitute about 20 percent of all the plasma proteins. ⚫ All the immunoglobulins are composed of combinations of light and heavy polypeptide chains. ⚫ Most are a combination of two light and two heavy chains
  15. 15. Schematic structure of an antibody: two heavy chains (blue, yellow) and the two light chains (green, pink). The antigen binding site is circled.
  16. 16. ⚫ The variable portion is different for each specific antibody, and it is this portion that attaches specifically to a particular type of antigen. ⚫ A combination of noncovalent and covalent bonds (disulfide) holds the light and heavy chains together. ⚫ Antibodies have more than one antigen combining site ⚫ Some bivalent Ab molecules can combine to form multimeric Abs that have upto 10 combining sites
  17. 17. Classes of Antibody ⚫ There are five general classes of antibodies, respectively named  IgM  IgG  IgA  IgD  IgE ⚫ IgG, which is a bivalent antibody and constitutes about 75 percent of the antibodies of the normal person.
  18. 18. Different Antibody structures
  19. 19. Antibody Isotype Location IgA Found in mucosal areas, such as the gut, respiratory tract and urogenital tract. IgD It has been shown to activate basophils and mast cells to produce antimicrobial factors IgE Binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Also protects against parasitic worms IgG Provides the majority of antibody-based immunity against invading pathogens. The only antibody capable of crossing the placenta to give passive immunity IgM Eliminates pathogens in the early stages of B cell-mediated immunity before there is sufficient IgG.
  20. 20. Antibody class switching ⚫ Class switching is the process whereby an activated B cell changes its antibody production from IgM to either IgA, IgG, or IgE depending on the functional requirements. ⚫ As antibody class is determined by the heavy chain of the antibody, class switching is done by replacing the heavy chain in the constant region of the antibody and leaving the antigen binding variable region as such.
  21. 21. How class switching happens ⚫ This is done by a process called class switch recombination and is an irreversible process. ⚫ A process occur whereby the constant region gene is swapped from μ (IgM) to one of the other isotypes, without altering the variable heavy chain gene expression.
  22. 22. What determines which class of antibody is expressed? ⚫ CD4 T cells in the area produce different cytokines and these cytokines interact with the B cells and cause them to favour a particular antibody class. For example, at mucosal surfaces, CD4 T cells will often produce TGFβ which drives the B cells present to produce IgG & IgA, whereas in allergy or during parasite infection there is a large amount of IL-4 and IL-13 which skew towards IgE production.
  23. 23. Mechanism of action of antibody ⚫ Antibodies act mainly in two ways to protect the body against invading agents:  (1) by direct attack on the invader and  (2) by activation of the “complement system” that then destroys the invader.
  24. 24. Direct Action of Antibodies ⚫ The antibodies can inactivate the invading agent in one of several ways, as follows: 1. Agglutination, in which antibodies "glue together" foreign cells into clumps that are attractive targets for phagocytosis 2. Precipitation, antigen (such as tetanus toxin) and antibody becomes so large that it is rendered insoluble and precipitates 3. Neutralization, in which the antibodies cover the toxic sites of the antigenic agent 4. Lysis, antibodies are occasionally capable of directly attacking membranes of cellular agents and thereby cause rupture of the agent
  25. 25. COMPLEMENT SYSTEM FOR ANTIBODY ACTION ⚫ The complement system is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism ⚫ “Complement” is a collective term that describes a system of about 30 proteins found in the blood, ⚫ synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). ⚫ The principal actors in this system are 11 proteins designated C1 through C9, B, and D,
  26. 26. Activation of complement system ⚫ Activated by binding of antigen & antibody ⚫ Followed by series of reactions ( Cascade) ⚫ Initial components acts as enzymes for the next step. ⚫ Two biochemical pathways activate the complement system:  the classical complement pathway,  the alternative complement pathway,
  27. 27. Classical complement pathway ⚫ The classical pathway is initiated by an antigen- antibody reaction. ⚫ The antigen-antibody complex binds directly with the C1 molecule of the complement system, setting into motion a “cascade” of sequential reactions,
  28. 28. The Classical complement pathway C1 C1 C4 + C2 C4b2b + C4a C3 C3b + C3a C5 C5b + C5a C6 + C7 C5b67 C8 + C9 C5b6789 Antigen – antibody complex
  29. 29. The Alternate complement pathway ⚫ Also known as the Properdin Pathway ⚫ Part of innate immunity ⚫ Bypasses C1, C4, and C2 ⚫ Does not require an antigen-antibody complex for its activation. ⚫ Does not wait for antibody to be formed for activation ⚫ Acts synergistically with the classical pathway ⚫ Usually activated by microorganisms and their toxins. eg. bacteria, viruses, damaged tissue.
  30. 30. The Alternate complement pathway C3 C3b + C3a C5 C5b + C5a C6 + C7 C5b67 C8 + C9 C5b6789 C1 C1 C4 + C2 C42 + C4a Antigen – antibody complex Microorganism (bacteria, virus etc)
  31. 31. Effects of complement activation 1. Opsonization and phagocytosis. One of the products of the complement cascade, C3b, strongly activates phagocytosis by both neutrophils and macrophages, causing these cells to engulf the bacteria to which the antigen-antibody complexes are attached. This process is called opsonization. Opsonin  A substance that promotes the phagocytosis of antigens by binding to them.
  32. 32. 2. Lysis. One of the most important of all the products of the complement cascade is the lytic complex, C5b6789 known as Membrane Attack Complex (MAC)  This has a direct effect of rupturing the cell membranes of bacteria or other invading organisms.  PNH 3. Neutralization of viruses. The complement enzymes and other complement products can attack the structures of some viruses and thereby render them nonvirulent.
  33. 33. 4. Chemotaxis. Fragment C5a initiates chemotaxis of neutrophils and macrophages, thus causing large numbers of these phagocytes to migrate into the tissue area adjacent to the antigenic agent. 5. Activation of mast cells and basophils. Fragments C3a, C4a, and C5a activate mast cells and basophils, causing them to release histamine, heparin, and several other substances into the local fluids. 6. Inflammatory Effect
  34. 34. C1 C1 C4 + C2 C42 + C4a C3 C3b + C3a C5 C5b + C5a C6 + C7 C5b67 C8 + C9 C5b6789 (MAC) Antigen – antibody complex Opsonization of bacteria Activate mast cell and basophil Chemotaxis of WBC Lysis of cells Microorganism (bacteria, virus etc)
  35. 35. Scanning electron micrographs of E. coli showing (a) intact cells and (c) cells killed by complement-mediated lysis. Membrane Attack Complex Attached to the bacterial cell membrane
  36. 36. Antigen presenting cells. ⚫ B lymphocyte, T lymphocytes respond to antigens only when they are bound to surface of antigen- presenting cells. ⚫ The three major types of antigen presenting cells are macrophages, B lymphocytes, and dendritic cells. ⚫ The dendritic cells, the most potent of the antigen- presenting cells, are located throughout the body, and their only known function is to present antigens to T cells.
  37. 37. ⚫ specific molecules called MHC proteins (Major histocompatibility Complex) are present on the surface of antigen presenting cells which bind to antigen. ⚫ There are two types of MHC proteins: 1. MHC I proteins, which present antigens to cytotoxic T cells, and 2. MHC II proteins, which present antigens to T-helper cells.
  38. 38. Activation of T cells requires interaction of T-cell receptors with an antigen that is transported to the surface of the antigen-presenting cell by a major histocompatibility complex (MHC) protein
  39. 39. T- Lymphocyte ⚫ Lymphoid progenitor cells pre-processed in the thymus gland, are called “T” lymphocytes to designate the role of the thymus. ⚫ They are responsible for cell-mediated immunity. ⚫ there are thousands of different types of thymic lymphocytes with specific reactivity against many thousands of different antigens.
  40. 40. ⚫ The thymus makes certain that any T lymphocytes leaving the thymus will not react against the body’s own tissues. ⚫ About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection
  41. 41. Positive selection of ‘T’ Lymphocyte. ⚫ Positive selection "selects for" T cells capable of interacting with MHC. ⚫ Thymocytes move deep into the thymic cortex, where they are presented with self-antigens by MHC. ⚫ Only those thymocytes that interact with MHC-I or MHC-II appropriately (i.e., not too strongly or too weakly) will receive a vital "survival signal".
  42. 42. ⚫ All that cannot (i.e., if they do not interact strongly enough, or if they bind too strongly) will die by "death by neglect" (no survival signal). ⚫ This process ensures that the selected T-cells will have an MHC affinity that can serve useful functions in the body ⚫ A thymocyte cells that interact well with MHC class II molecules will eventually become CD4+ or T helper cells, ⚫ A thymocytes that interact well with MHC class I molecules mature into CD8+ or cytotoxic T cells.
  43. 43. Negative selection of ‘T’ Lymphocyte. ⚫ Negative selection removes thymocytes that are capable of strongly binding with "self" MHC peptides. ⚫ Thymocytes that survive positive selection migrate towards medulla in the thymus. ⚫ In the medulla, they are again presented with a self-antigen presented on the MHC. ⚫ Thymocytes that interact too strongly with the self- antigen receive an apoptotic signal that leads to cell death.
  44. 44. ⚫ This process of negative selection is an important component of central tolerance and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host. ⚫ Thus T cells that leave the thymus are self- restricted, self-tolerant, and just around 3-4% of the total thymocyte.
  45. 45. Types of T Cells ⚫ T cells are classified into three major groups: 1. T-helper cells, 2. Cytotoxic T cells, and 3. Suppressor T cells.
  46. 46. T-Helper Cells ⚫ The most numerous of the T cells, usually constituting more than three quarters of all of them. ⚫ Help in the functions of the immune system, as the major regulator of virtually all immune functions. ⚫ Secrete protein mediators, called lymphokines, that act on other cells of the immune system and bone marrow cells.
  47. 47. The most important lymphokines secreted by the T-helper cells are: ⚫ Interleukin-2 ⚫ Interleukin-3 ⚫ Interleukin-4 ⚫ Interleukin-5 ⚫ Interleukin-6 ⚫ Granulocyte-monocyte colony-stimulating factor ⚫ Interferon-γ
  48. 48. Functions of T-helper cells. ⚫ Stimulation of growth and proliferation of Cytotoxic T Cells and Suppressor T Cells. The lymphokine interleukin-2 has an especially strong stimulatory effect in causing growth and proliferation of both cytotoxic and suppressor T cells ⚫ Stimulation of B-Cell growth and differentiation to form Plasma cells and Antibodies. Almost all the interleukins participate in the B-cell response, especially interleukins 4, 5, and 6.
  49. 49. ⚫ Activation of the Macrophage System Lymphokines cause chemotaxis and activate the macrophages to cause far more efficient phagocytosis, allowing them to attack and destroy increasing numbers of pathogens. ⚫ Feedback Stimulatory Effect on the T-Helper Cells interleukin-2, have a direct positive feedback effect in stimulating activation of the T-helper cells thus amplifying the helper cell response
  50. 50. ⚫ It is the T-helper cells that are inactivated or destroyed by the human immunodeficiency virus (HIV). ⚫ This leaves the body almost totally unprotected against infectious disease, therefore leading to the now well known acquired immune deficiency syndrome (AIDS).
  51. 51. Cytotoxic T Cells ⚫ The cytotoxic T cell is a direct-attack cell that is capable of killing microorganisms and, at times, even some of the body’s own cells. ⚫ these cells are called killer T cells. ⚫ The receptor proteins on the surfaces of the cytotoxic cells cause them to bind tightly to the antigenic cell and kill it.
  52. 52. ⚫ the cytotoxic T cell secretes hole-forming proteins, called perforins, that literally punch round holes in the membrane of the attacked cell. ⚫ the cytotoxic T cell releases cytotoxic substances directly into the attacked cell. ⚫ Almost immediately, the attacked cell becomes greatly swollen and lysis of the cell happens.
  53. 53. Suppressor T Cells ⚫ They are capable of suppressing the functions of both cytotoxic and T-helper cells. ⚫ the suppressor T-cell system plays an important role in immune tolerance. ⚫ Since they regulate the function of other T cells they are now known as Regulatory T cells
  54. 54. Immunization ⚫ Acquired immunity can be actively generated by the use of immunization / vaccination. ⚫ Immunization is also called active acquired immunity or simply active immunity ⚫ Immunization has been used for many years to produce acquired immunity against specific diseases. ⚫ exposing a human, or an animal, to an immunogen in a controlled way, so that the body can learn to protect itself by mounting an appropriate immune response
  55. 55. ⚫ Immunization can be done by: 1. Injecting dead organisms that are no longer capable of causing disease but that still have some of their chemical antigens. This type of immunization is used to protect against typhoid fever, whooping cough, diphtheria, and many other types of bacterial diseases. 2. Injecting denatured toxins that have been treated with chemicals so that their toxic nature has been destroyed even though their antigens are still intact. This procedure is used in immunizing against tetanus, botulism, and other similar toxic diseases.
  56. 56. 3. Injecting live organisms that have been “attenuated.” This procedure is used to protect against yellow fever, poliomyelitis, measles, and many other viral diseases.
  57. 57. Passive immunity ⚫ Temporary immunity can be achieved in a person by injecting antibodies, activated T cells, or both obtained from the blood of someone else or from some other animal that has been actively immunized against the antigen. ⚫ Such transfusion of antibodies or T lymphocytes to confer immunity is called passive immunity. ⚫ Antibodies last in the body of the recipient for 2 to 3 weeks, and Activated T cells last from few hours to few weeks
  58. 58. Allergy And Hypersensitivity ⚫ An important undesirable side effect of immunity ⚫ an over-reaction of the immune system and these reactions may be damaging and uncomfortable. ⚫ Hypersensitivity reactions can be classified into four types.  Type I: IgE mediated immediate reaction  Type II: Antibody-mediated reaction (IgG or IgM antibodies)  Type III: Immune complex-mediated reaction  Type IV: Cytotoxic, cell-mediated, delayed hypersensitivity reaction
  59. 59. ALLERGY CAUSED BY ACTIVATED T CELLS: DELAYED-REACTION ALLERGY: ⚫ Delayed-reaction allergy is caused by activated T cells and not by antibodies. ⚫ upon repeated exposure of antigen the formation of activated helper and cytotoxic T cells happens . ⚫ the eventual result of delayed reaction allergies can be serious tissue damage. ⚫ The damage occurs in the tissue area where the instigating antigen is present,
  60. 60. “ATOPIC” ALLERGIES ASSOCIATED WITH EXCESS IgE ANTIBODIES ⚫ Some people have an “allergic” tendency. Their allergies are called atopic allergies because they are caused by a nonordinary response of the immune system. ⚫ The allergic tendency is characterized by the presence of large quantities of IgE antibodies in the blood. ⚫ These antibodies are called reagins or sensitizing antibodies to distinguish them from the more common IgG antibodies.
  61. 61. ⚫ A special characteristic of the IgE antibodies (the reagins) is a strong propensity to attach to mast cells and basophils. ⚫ Upon activation by a an allergen, IgE causes many of the mast cells and basophils to rupture; ⚫ This releases chemicals like histamine, protease, slow-reacting substance of anaphylaxis (which is a mixture of toxic leukotrienes), eosinophil chemotactic substance, neutrophil chemotactic substance, heparin, and platelet activating factors.
  62. 62. ⚫ These substances cause such effects as:  dilation of the local blood vessels;  attraction of eosinophils and neutrophils to the reactive site;  increased permeability of the capillaries withloss of fluid into the tissues; and  contraction of local smooth muscle cells.